Powders comprising anti-adherant materials for use in dry powder inhalers

ABSTRACT

A powder for use in a dry powder inhaler comprises active material and additive material. The additive material comprises an anti-adherent material and the powder includes at least 60% by weight of active material. The inclusion of the additive material in the powder has been found to give an increased respirable fraction of the active material.

BACKGROUND OF THE INVENTION

This application is a 371 of PCT/GB96/01783, filed Jul. 24, 1996.

This invention relates to powders for use in dry powder inhalers.

BRIEF SUMMARY OF THE INVENTION

Inhalers are well known devices for administering pharmaceuticalproducts to the respiratory tract by inhalation. Inhalers are widelyused particularly in the treatment of diseases of the respiratory tract.

There are a number of types of inhaler currently available. The mostwidely used type is a pressurised metered dose inhaler (MDI) which usesa propellant to expel droplets containing the pharmaceutical product tothe respiratory tract. Those devices are disadvantageous onenvironmental grounds as they often use CFC propellants, and on clinicalgrounds related to the inhalation characteristics of the devices.

An alternative device to the MDI is the dry powder inhaler. The deliveryof dry powder particles of pharmaceutical products to the respiratorytract presents certain problems. The inhaler should deliver the maximumpossible proportion of the active particles expelled to the lungs,including a significant proportion to the lower lung, preferably at thelow inhalation capabilities to which some patients, especiallyasthmatics, are limited. It has been found, however, that, whencurrently available dry powder inhaler devices are used, in many casesonly about 10% of the active particles that leave the device oninhalation are deposited in the lower lung. More efficient dry powderinhalers would give clinical benefits.

The type of dry powder inhaler used is of significant importance to theefficiency of delivery over a range of airflow conditions of the activeparticles to the respiratory tract. Also, the physical properties of thepowder used affect both the efficiency and reproducibility of deliveryof the active particles and the site of deposition in the respiratorytract.

On exit from the inhaler device, the active particles should form aphysically and chemically stable aerocolloid which remains in suspensionuntil it reaches a conducting bronchiole or smaller branching of thepulmonary tree or other absorption site preferably in the lower lung.Once at the absorption site, the active particle should be capable ofefficient collection by the pulmonary mucosa with no active particlesbeing exhaled from the absorption site.

The size of the active particles is particularly important. Foreffective delivery of active particles deep into the lungs, the activeparticles should be small, with an equivalent aerodynamic diametersubstantially in the range of 0.1 to 5 μm, approximately spherical andmonodispersed in the respiratory tract. Small particles are, however,thermodynamically unstable due to their high surface area to volumeratio, which provides significant excess surface free energy andencourages particles to agglomerate. In the inhaler, agglomeration ofsmall particles and adherence of particles to the walls of the inhalerare problems that result in the active particles leaving the inhaler aslarge stable agglomerates or being unable to leave the inhaler andremaining adhered to the interior of the inhaler.

The uncertainty as to the extent of formation of stable agglomerates ofthe particles between each actuation of the inhaler and also betweendifferent inhalers and different batches of particles, leads to poordose reproducibility.

In an attempt to improve that situation, dry powder for use in drypowder inhalers often include coarse carrier particles mixed with fineparticles of active material. The active particles adhere to thesurfaces of the carrier particles whilst in the inhaler device, and aredispersed on inhalation into the respiratory tract to give a finesuspension. The carrier particles are often large particles greater than90 μm in diameter to give good flow properties because small particleswith a diameter of less than 10 μm may become coated on the wall of thedelivery device and have poor flow and entrainment properties leading topoor dose uniformity.

There are, however, problems associated with the addition of carrierparticles to the active particles in the dry powder, for exampleproblems related to the efficient release of the active particles fromthe surfaces of the carrier particles on inhalation. Furthermore, insome cases it is preferred for no carrier particles to be present in thepowder administered.

In known dry powder inhaler devices, doses of powder containing onlyactive particles are dispensed. The powder contains no carrier particlesor other additives and the amount of powder in each dose is small,usually less than 1 mg. The volume of the dose may be, for example,approximately 6.5 μl.

Problems involved in dispensing a powder containing only particles ofactive material include

(i) formation of stable agglomerates of the small particles which oftenare not broken down into individual particles in the airstream when theparticles are inhaled and are, therefore, less likely to reach the lowerlung on inhalation of the powder than the fine individual activeparticles;

(ii) variations in the amount of powder metered from a reservoir of theinhalation device due to poor flow properties of the powder andinconsistent agglomeration, leading to inconsistency in the size ofdose, which may vary as much as ±50% compared with the nominal dose forthe device;

(iii) incomplete removal of the dose from the device due to adherence ofthe particles to the walls of the device, leading to poor dosereproducibility.

An object of the present invention is to provide a dry powder for use indry powder inhalers which overcomes or mitigates at least one of theabove disadvantages.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a sectional view of a dry powder inhaler

FIG. 2 is a sectional diagram of a twin stage impinger

DETAILED DESCRIPTION

According to the invention, there is provided a powder for use in a drypowder inhaler, the powder comprising active material and additivematerial, the additive material comprising an anti-adherent material andthe powder including at least 60% by weight of active material based onthe weight of the powder.

A purpose of the additive material is to hinder the formation of stableagglomerates of the active material in the powder. As indicated above,stable agglomeration of the active particles with the known powders maylead to decreased deposition of the active material in the lower lung,together with poor dose uniformity. That is because, when the smallactive particles agglomerate, the agglomerates which are formed may havea diameter of 100 μm or more. If those agglomerates do not break up whenthe powder is inhaled, they are unlikely to reach the lower lung due totheir size.

The addition of the anti-adherent material decreases the cohesionbetween the particles of the powder containing the active material. Itis thought that the additive material interferes with the weak bondingforces, such as Van der Waal's and Coulomb forces, between the smallparticles, helping to keep the particles separated and may be thought ofas weak links or “chain breakers” between the particles. Adhesion of theparticles to the walls of the device is also reduced. Where agglomeratesof particles are formed, the addition of the additive material decreasesthe stability of those agglomerates so that they are more likely tobreak up in the turbulent airstream created on inhalation to form smallindividual particles which are likely to reach the lower lung.

The reduced tendency of the particles to bond strongly either to eachother or to the device itself, reduces powder cohesion and adhesion andpromotes better flow characteristics which leads to improvements in thedose reproducibility by reducing the variation in the amount of powdermetered out for each dose and improving the release of the powder fromthe device as well as increasing the likelihood that the active materialwhich does leave the device will reach the lower lung of the patient.

It is thought that it is favourable for unstable agglomerates ofparticles to be present in the powder when it is in the inhaler device.As indicated above, for a powder to leave an inhaler device efficientlyand reproducibly, the particles of such a powder should be large,preferably larger than 45 μm. Such a powder may be in the form of eitherindividual particles having a size of 45 μm or larger and/oragglomerates of finer particles, the agglomerates having a size of 45 μmor larger. The agglomerates formed can have a size of as much as 100 μmand, with the addition of the additive material, those agglomerates aremore likely to be broken down efficiently in the turbulent airstreamcreated on inhalation. Therefore the formation of unstable agglomeratesof particles in the powder may be favoured compared with a powder inwhich there is substantially no agglomeration.

The reduction in the cohesion and adhesion between the active particlescould lead to equivalent performance with reduced agglomerate size, oreven with individual particles.

Where reference is made to anti-adherent materials, the reference is toinclude those materials which will decrease the cohesion between theparticles of the powder. Those materials will include those usuallythought of as anti-adherent materials, for example leucine, as well asothers, for example, lecithin, which are not generally thought of asbeing anti-adherent but may nonetheless have the effect of decreasingthe cohesion between the particles of the powder. Other materialscommonly added to powders for use in inhalers, for example lactose andvarious other carrier particle materials, are not anti-adherentmaterials per se but might be added to a powder in addition to asuitable anti-adherent material, for example leucine as indicated below.

Furthermore, many materials are not suitable anti-adherent materialsbecause they are “sticky” and tend to increase cohesion betweenparticles. For example, fatty acids, increase stickiness in powders andare thought to be unsuitable as the additive material. Also, othermaterials such as sorbitan esters (for example SPAN 85) and cyclodextrins are not suitable anti-adherent materials.

It is possible that materials which are anti-adherent for one type ofactive material, will not be anti-adherent for a different type. Asuitable test to determine whether or not an additive material isanti-adherent is as follows.

The “Aeroflow” apparatus of Amherst Process Instruments Incorporated ofMountain Farms Technology Park, Hadley, Mass. 01035-9547 U.S.A., is usedto assess whether a material is anti-adherent.

The Aeroflow apparatus is used to measure the flow properties ofpowders. A sample of powder is placed in a perspex cylinder which isrotated at a speed of about 5 rpm about a horizontal axis. As thecylinder rotates, the powder will tend to form a pile of powder whichextends around the inner surface of the cylinder as powder material iscarried round by the rotating cylinder. When the height of the pilereaches a certain level, powder material from the top of the pileavalanches down towards the bottom of the pile. Thus as the cylinderrotates, the powder will avalanche at a frequency dependent on theproperties of the powder. For a freely flowing powder material, the timebetween avalanches will be low whereas for a cohesive material, the timebetween avalanches will be great.

The general procedure for the test is as follows:

(a) A powder for testing is made by mixing together active material andadditive material as described in (i) or (ii) below to form a powdercontaining the concentration by weight of additive material of thepowder to be tested. The particles of the powder are agglomerated bymixing the particles for 10 minutes at a relative humidity of 55% in atumbling blender, preferably a Turbula mixer.

(i) Where the additive material is in the form of particles, blend theactive and additive materials together,

(ii) where the additive material is to form a coating on the surfaces ofthe active particles as described below, the additive material is addedto the active particles from suspension or from solution and theresulting powder is dried and divided.

(b) A 200 g sample of the powder obtained in (a) above is put into theAeroflow apparatus and the mean time between avalanches is measured asthe cylinder is rotated.

(c) (b) above is repeated for a sample of active material which has beenprepared as in (a) above except that no additive material is added.

For a material which is to be taken as an anti-adherent material for thepurposes of this invention, the mean time between avalanches will belower for the material containing the additive material, indicatingimproved flow properties and less cohesion.

For additive materials comprising a fatty acid, the time betweenavalanches is greater when the fatty acid has been added to thematerial. Thus fatty acids are unsuitable for use as the anti-adherentmaterial.

Where it is indicated that a material is not anti-adherent, thatmaterial might be added to the active material, for example as adiluent, provided that a suitable anti-adherent additive material isalso added such that the resulting effect of the additive material andthe diluent is anti-adherent. Where further components other than theactive material and the anti-adherent material are included in thepowder, advantageously the complete powder also “passes” the above testin that the combined effect of all of the components added to the activematerial is that of an anti-adherent material.

Advantageously, the powder comprises at least 70%, more preferably atleast 80% by weight of active material based on the weight of thepowder. Most advantageously, the powder comprises at least 90%, morepreferably at least 95%, more preferably at least 97%, by weight ofactive material based on the weight of the powder. It is believed thatthere are physiological benefits in introducing as little powder aspossible to the lungs, in particular material other than the activeingredient to be administered to the patient. Therefore, the quantitiesin which the additive material is added are preferably as small aspossible. The most preferred powder, therefore, would comprise more than99% by weight of active material.

Advantageously, at least 90% by weight of the particles of the powderhave a particle size less than 63 μm, preferably less than 30 μm andmore preferably less than 10 μm. As indicated above, the size of theparticles of the powder should be within the range of about from 0.1 μmto 5 μm for effective delivery to the lower lung. Where the additivematerial is in the form of particles of material, as is described below,it may be advantageous for particles of the additive material to have asize outside the preferred range for delivery to the lower lung.

As indicated above, in some cases it will be preferred for the particlesto be in the form of agglomerates in the powder. In such cases, theparticle sizes indicated above are those of the individual particlesmaking up the agglomerates.

It will be appreciated that the chemical composition of the additivematerial is of particular importance.

Advantageously, the additive material comprises physiologicallyacceptable material. Clearly, it is highly preferable for the additivematerial to be a material which may be safely inhaled into the lowerlung, where it would usually be absorbed into the blood stream. Theadditive material should therefore be one which is safe to administer byinhalation. The additive material may include a combination of one ormore materials.

Advantageously, the additive material includes one or more compoundsselected from amino acids and derivatives thereof, and peptides andpolypeptides having a molecular weight of between about 0.25 to 1000kDa, and derivatives thereof. Amino acids, peptides and polypeptides andtheir derivatives are physiologically acceptable and act asanti-adherent materials when added to the active material. It isparticularly advantageous for the additive material to comprise an aminoacid. Amino acids have been found to give, when present as additivematerial, high respirable fraction of the active material and also goodflow properties of the powder. A preferred amino acid is leucine, inparticular L-leucine. Whilst the L-form of the amino acids is preferredin the Examples, the D- and DL-forms may also be used. The additivematerial may comprise one or more of any of the following amino acids:leucine, isoleucine, lysine, valine, methionine, cysteine,phenylalanine.

As indicated above, the additive material may include derivatives ofamino acids or peptides. For example the additive material may be a saltor an ester, for example aspartame, or may be N acetyl-L cysteine. Theadditive material may comprise salts such as acesulfame K or othersweeteners, for example saccharin sodium or a cyclamate.

The additive material may include one or more water soluble compounds.Those compounds, if they penetrate into the deep lung may therefore beabsorbed into the blood stream, which is advantageous.

The additive material may include one or more surface active materialswhich may be water soluble, for example, lecithin, in particular soyalecithin. Lecithin is not an especially preferred additive materialbecause it is thought that at least in some cases it could giveincreased cohesion in the powder material.

The additive material may include dipolar ions which may be zwitterions.

Advantageously, the additive material includes a glidant material. Aglidant material is one that will decrease the resistance to sliding ofthe particles. The addition of a glidant material, therefore, will leadto improved release of the powder from the inhaler device and thereforebetter dose uniformity. The glidant materials which have this effectwill include those usually thought of as glidants as well as those notusually thought of as glidants but which have a glidant effect whenadded to the active material. Many of the anti-adherent materialsdescribed above are also glidants. The glidant material may, therefore,be the same compound as that of the anti-adherent material, or may be adifferent compound or a mixture of compounds.

The active material referred to throughout the specification will bematerial comprising one or a mixture of pharmaceutical products. It willbe understood that the term “active material” includes material which isbiologically active, in the sense that it is able to decrease orincrease the rate of a process in a biological environment. Thepharmaceutical products include those products which are usuallyadministered orally by inhalation for the treatment of disease such asrespiratory disease e.g. β-agonists, salbutamol and its salts orsalmeterol and its salts. Other pharmaceutical products which could beadministered using a dry powder inhaler include peptides andpolypeptides, such as DNase, leucotrienes and insulin.

The active material may include a β₂-agonist, which may includesalbutamol, a salt of salbutamol or a combination thereof. Salbutamoland its salts are widely used in the treatment of respiratory disease.The active material may be salbutamol sulphate. The active material maybe terbutaline, a salt of terbutaline, for example terbutaline sulphate,or a combination thereof. Terbutaline sulphate is of particularimportance. The active material may be ipatropium bromide.

The active material may include a steroid, which may be beclomethasonedipropionate or may be fluticasone. The active material may include acromone which may be sodium cromoglycate or nedocromil or its salts. Theactive material may include a leukotriene receptor antagonist.

The active material may include a carbohydrate, for example heparin.

Advantageously, the powder comprises particles of active material andparticles of additive material. Where particles of additive material areused, by choosing a particular size of the additive particles, asdescribed below, the amount of additive material entering the lower lungmay be minimised. Also, it may be preferable for the additive to bepresent in the powder as particles rather than, for example, a coatingaround the particles of active material which may hinder the absorptionof the active material into the blood stream.

Advantageously, at least 90% by weight of the additive particles have aparticle size less than 63 μm, preferably, less than 30 μm, and morepreferably less than 10 μm. The additive particles will usually have aparticle size slightly larger than the particle size of the activeparticles to encourage deposition of the additive particles in the upperairways. To restrict the amount of the additive material penetrating tothe deep lung on inhalation, it is advantageous to include additiveparticles having a size greater than 5 μm. The size of the particles maybe calculated by laser diffraction or other method by which theaerodynamic diameter of the particles can be determined.

The additive particles may be non-spherical in shape. The additiveparticles may be plate-like particles, for example leucine particles.Alternatively the additive particles may be angular, for example prisms,or dendritic in shape, for example aspartame particles. Plate-likeparticles may give improved surface interaction and glidant actionbetween the surfaces of the active particles thereby decreasing bondingbetween the active particles and reducing stable agglomeration.

Alternatively, for example where the nature of the additive material issuch that small particles are not easily formed, or for clinicalreasons, the additive material may form at least a partial coating onthe surfaces of particles of the active material. It is found that evenwhen a large amount of the additive material is added to the activematerial, there is no “coating” of the active particles in the sense inwhich that word would normally be used in the art, namely to refer to acontinuous envelope around the active particle. Instead, a discontinuouscovering is formed on the active particle. It is believed that thepresence of such a discontinuous covering, as opposed to a “coating” isan important and advantageous feature of the present invention.

Additive material may be present in the powder both in the form of smallparticles and in the form of a coating on the surfaces of the particlesof active material.

Where the additive material is to form a coating on the surfaces of theparticles of active material, the additive material may be added to theactive material from a suspension or from solution. The additivematerial may be added to the active material by co-crystallisation,co-spray drying, co-granulation or other similar method.

Where the additive is in the form of particles, the powder may beproduced by, for example, blending together micronised active materialand micronised additive material. Alternatively, the components of thepowder may be micronised together to form the powder material.

The ratio in which the additive material and the active material arepresent in the powder will depend on the type of inhaler device used,the type of active material used and the required dose. Usually, thepowder comprises at least 0.1% by weight of additive material based onthe weight of the powder. The powder preferably comprises between about0.1% and 40%, more preferably between about 0.25% and 5% by weight ofadditive material based on the weight of the active material.

It has been found that the addition of more additive material does notnecessarily give a greater improvement in the properties of theresulting powder. For example, in the case where the additive materialis leucine as in Example 8 below, the addition of 1% by weight ofleucine gives good results, but the addition of 5% or 10% by weight ofleucine does not give better results, indeed the respirable fraction isseen to decrease with increased addition of leucine.

Furthermore, because the additive material will in many cases be inhaledinto the lung, it is preferable for only a small amount of additivematerial to be added.

The optimum amount of additive material in the powder will depend on theactive material and additive material used. Advantageously, the powdercomprises not more than 8% by weight, preferably not more than 5% byweight, of additive material. In some cases it will be advantageous forthe powder to contain about 1% by weight of additive material.

Advantageously, at least 95% by weight of the active particles have aparticle size less than 10 μm. Preferably, at least 95% by weight of theactive particles have a particle size between about 0.1 μm and 10 μm,more preferably between about 0.1 μm and 5 μm. The particles willtherefore give a good suspension on release from the inhaler device anddelivery of the active particles deep into the respiratory tract. Thesize of the particles may be calculated as described above in respect ofthe additive particles.

The powder may also contain, for example, flavourings and colourantmaterials and may also contain diluents. Advantageously the powderincludes less than 20% preferably less than 10%, more preferably lessthan 1%, by weight of constituents other than the active material andthe anti-adherent material.

According to the invention, there is also provided a powder for use in adry powder inhaler the powder comprising active particles and additivematerial, at least 90% by weight of the powder particles having aparticle size of less than 63 μm, the powder including at least 60% byweight of active particles based on the weight of the powder.

Advantageously, at least 90% by weight of the powder particles have aparticle size of less than 30 μm, preferably less than about 10 μm.Advantageously, the powder includes at least 80%, preferably at least90% by weight of active particles based on the weight of the powder.

Advantageously, the powder includes not more than 8%, moreadvantageously not more than 5% by weight of additive material based onthe weight of the powder. As indicated above, in some cases it will beadvantageous for the powder to contain about 1% by weight of additivematerial.

As indicated above, the additive material may be in the form ofparticles.

The invention also provides, a powder for use in a dry powder inhaler,the powder comprising active particles and additive material, theadditive material forming at least a partial coating on the surfaces ofthe particles of active material, the powder including at least 60% byweight of active material based on the weight of the powder, at least90% by weight of the particles of the powder having a particle size lessthan 63 μm.

Advantageously, the powder includes at least 80%, preferably at least90% by weight of active material based on the weight of the powder.

According to the invention, there is also provided a dry powder inhalerincluding a powder as described above.

Advantageously, the inhaler may be activated to dispense a dose of lessthan 10 mg of the powder, preferably not more than 5 mg, more preferablynot more than 1 mg. Obviously, the size of the dose will depend on theactive material to be delivered and the inhaler device used.

The invention also provides a dose of powder, the dose containing notmore than 5 mg of powder described above, more preferably not more than1 mg of the powder.

The invention also provides the use of an anti-adherent additivematerial in a powder for use in a dry powder inhaler, for improving theflow characteristics of the powder, the powder comprising at least 60%by weight of active material based on the weight of the powder. The testto assess whether a material is an anti-adherent material is indicatedabove.

Unless it is clear from the context otherwise, where reference is madeto a range of sizes of particles, and to the size of particles, it is tomean that the majority of the relevant particles are within that rangeor are of that size. Preferably at least about 90% by weight of therelevant particles will be in that range or be of that size, morepreferably at least 95% by weight.

The size of particles may, where appropriate be selected and/or measuredusing a sieving method. Otherwise, the size of the particles may bedetermined using laser light diffraction, or other method in which theaerodynamic diameter of the particles may be determined, for examplemicroscopic image analysis.

One of the objects of the invention is to hinder the formation of stableagglomerates of particles, especially active particles, in the powder.However, as described above, it may be desirable for unstableagglomerates to be formed in the powder, and the size of thoseagglomerates may be as large as 100 μm or more. The size of particles inthe powder, when considering the agglomerates, is to be taken as thesize of the individual particles making up the agglomerate. The sizes ofthe individual particles may be determined using microscopic imageanalysis.

Embodiments of the invention will now be described by way of examplewith reference to the accompanying drawings of which:

FIG. 1 shows a view of a dry powder inhaler device known as a Turbohaler(Trade Mark). The Turbohaler is a breath actuated inhaler which may beused to meter out and deliver small quantities of dry powder. The massof powder delivered for each inhalation is often less than 1 mg.

As shown in FIG. 1, the Turbohaler comprises an outer cylindrical body 2which has a mouthpiece 3 around one end and a rotatable base 4 at theother end. The body 2 houses a storage chamber 5 for storing the drypowder to be dispensed, and a dosing disc 6 under the storage chamber.The dosing disc 6 includes a number of identical cavities around itsedge.

Rotation of the base 4 causes rotation of the disc 6 and the cavitiespass under the storage chamber 5 and are filled with a volume of the drypowder material. Forcible filling of the cavities, in an attempt toreduce variability in the amount of powder filled into the cavities, isachieved by the provision of scrapers above the cavities and a pressureplate below the dosing disc urging the disc 6 towards the storagechamber 5. The base 4 is rotated backwards and forwards to dispense thepowder into the cavities.

Rotation of the disc 6 also brings successive cavities in and out ofcommunication with a channel 8 which leads from the disc 6 to themouthpiece 3.

To administer the powder, a filled cavity is brought into alignment withthe channel 8 and a patient inhales through the mouthpiece 3. Air isdrawn into the body via an inlet 7 (and other inlets) and the air passesthrough a hole in the pressure plate and through holes in the bottom ofthe cavity thereby discharging the contents of the cavity into thechannel 8. The powder is inhaled via the mouthpiece 3.

To increase the turbulent airflow in the device, to help break up anyagglomerates of powder, the device includes other inlets in the body 2.The mouthpiece includes channels 9 to increase turbulence.

The storage chamber usually has the capacity to hold approximately 200doses of the powder and, when empty, may be refilled or disposed of.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Examples of suitable powders according to the invention, which may beused in a Turbohaler are as follows. Whilst the Examples refer to use ofthe powders in a Turbohaler, powders according to the invention mayinstead be used in other suitable devices, for example, a MIAT-Haler.

EXAMPLE 1

2 g leucine powder was mixed with 198 g terbutaline sulphate powder in aTurbula mixer for approximately 15 minutes. Before mixing, the particlesof the terbutaline sulphate had a mass median aerodynamic diameter(MMAD) of 2.1 μm, and 95% by weight of the leucine powder had a particlesize less than 150 μm (at least 95% by weight passes through a 150 μmmesh sieve).

The resulting powder was agglomerated using a milling procedure. 50 gsamples of the powder were milled in a porcelain ball mill (manufacturedby Pascall Engineering Company) having a diameter of approximately 150mm, using steel grinding balls. The milling was continued for about 6hours. The agglomerated powder was filled into a Turbohaler in a knownway.

Each metered dose for inhalation from the Turbohaler containedapproximately:

500 μg terbutaline sulphate  5 μg leucine.

An approximate value for the volume of the metered dose might be 6.5 μl.

EXAMPLE 2

2 g leucine powder was mixed with 198 g terbutaline sulphate powder asdescribed in Example 1. The powder mixture was filled into aTurbo-haler.

Each metered does for inhalation from the Turbohaler containedapproximately

500 μg terbutaline sulphate  5 μg leucine

An approximate value for the volume of the metered dose might be 6.5 μl.

EXAMPLE 3

4 g of leucine powder was mixed with 196 g terbutaline sulphate powderas described above for Example 1. The resulting powder was agglomeratedusing a milling procedure as described for Example 1 and filled into aTurbohaler.

Each metered dose for inhalation from the Turbohaler containedapproximately

500 μg terbutaline sulphate  10 μg leucine

EXAMPLE 4

1 g soy lecithin (95% by weight of particles less than 710 μm) wasdissolved in 10 g water and 10 g IMS (or in 20 g 95% ethanol) and addedto 199 g terbutaline sulphate powder (MMAD 2.1 μm) in a high shearmixer. The mixture was blended for four minutes and then dried on traysat 40° C. for 6 hours. The powder was screened through a 500 μm sievethen milled in a ball mill using steel balls, as described for

Example 1, for six hours to cause agglomeration. The agglomerated powderwas filled into a Turbohaler.

Each metered dose for inhalation from the Turbohaler containedapproximately

 500 μg terbutaline sulphate  2.5 μg soy lecithin

EXAMPLE 5

Agglomerated powder was prepared as for Example 3 above except that 4 gsoy lecithin (95% by weight of particles less than 710 μm) was dissolvedin 10 g water and 10 g IMS and added to 196 g terbutaline sulphatepowder (MMAD 2.1 μm). The agglomerated powder was filled into aTurbohaler.

Each metered dose for inhalation from the Turbohaler containedapproximately

500 μg terbutaline sulphate  10 μg soy lecithin

EXAMPLE 6

1 g solid state soy lecithin having 95% by weight of particles having asize less than 100 μm were added to 199 g terbutaline sulphate (MMAD 2.1μm) and mixed in a Turbula mixer for approximately 15 minutes. Theresulting powder was agglomerated by ball milling as described inExample 1. The agglomerated powder was filled into a Turbohaler.

Each metered dose for inhalation from the Turbohaler containedapproximately

 500 μg terbutaline sulphate  2.5 μg soy lecithin

EXAMPLE 7

A powder for inhalation using a Turbohaler was prepared by mixing 199 gbudesonide and 1 g L-leucine as described above for Example 1. Thepowder was agglomerated as described for Example 1 and filled into theTurbohaler in a known way.

Each metered dose for inhalation from the Turbohaler containedapproximately:

 100 μg budesonide  0.5 μg L-leucine

It will be understood that the Turbohaler device described above is onlyan example of a dry powder inhaler device which may be used to dispensepowder according to the invention, and that different dry powder inhalerdevices may be used.

The efficiency of the delivery of the active particles to the lungs of apatient by the inhaler device, and the dose reproducibility achieved,may be assessed using a twin stage impinger (TSI) as described below.

FIG. 2 shows a diagrammatic arrangement of a TSI.

The TSI is a two stage separation device used in the assessment of oralinhalation devices. Stage one of the apparatus is shown to the right ofthe line AB in FIG. 2 and is a simulation of the upper respiratorytract. To the left of that line is stage two which is a simulation ofthe lower respiratory tract.

The TSI comprises a mouth 21 which comprises a polydimethylsiloxaneadaptor, moulded to accept the mouthpiece of the inhaler device, uppertubing 22 and upper impinger 23 to simulate the upper respiratory tract,the upper impinger containing liquid 24, and lower tubing 25 and lowerimpinger 26 to simulate the lower respiratory tract, the lower impingercontaining liquid 27. The lower impinger 26 is connected via an outletpipe 28 to a pump 29 which draws air through the TSI apparatus at apredetermined rate. The base of the lower tubing 25 is at the level ofthe liquid 27 such that all the air drawn through the TSI bubblesthrough the lower liquid 27. The liquid used in both the upper and lowerimpinger is distilled water.

In use, the inhaler is placed in a mouth 21 of the TSI. Air is caused toflow through the apparatus by means of a pump 29 which is connected tostage two of the TSI. Air is sucked through the apparatus from the mouth21, flows through upper tubing 22 via the upper impinger 23 and thelower tubing 25 to the lower impinger 26 where it bubbles through liquid27 and exits the apparatus via outlet pipe 28. The liquid 24 in theupper impinger 23 traps any particle with a size such that it is unableto reach stage two of the TSI. Fine particles, which are the particlesable to penetrate to the lungs in the respiratory tract, are able topass into stage two of the TSI where they flow into the lower impingerliquid 27.

30 ml of distilled water is put into the lower impinger 26 and 7 ml ofdistilled water is put into the upper impinger 23. The lower tubing 25is arranged such that its lower end is at the level of the water in thelower impinger 26. The pump 29 is adjusted to give an air flow rate of60 liters per minute in the apparatus.

The Turbohaler inhaler device is weighed. The mouthpiece 3 of theinhaler is connected to the mouth 21 of the TSI, the base 4 is rotatedto dispense a dose of powder and the pump is switched on and timed for aperiod of ten seconds. The pump is then switched off and the Turbohaleris removed from the TSI, reweighed and the amount of powder lost fromthe inhaler calculated.

The sections of the apparatus making up stage one of the TSI are washedinto a second flask and made up to 250 ml with distilled water. Thesections making up the second stage of the TSI are washed into a thirdflask and made up to 100 ml with distilled water.

The test is repeated several times to assess the dose reproducibility.

The amount of active substance in each section of the TSI is measuredfor each test. For example, when the active substance is budesonide asfor the Examples below, the following method may be used.

The contents of the flasks containing the washing from the stages of theTSI are assayed using High Performance Liquid Chromatography (HPLC)analysis for the content of budesonide and compared against standardsolutions containing 0.5 μg/ml and 1 μg/ml of budesonide.

The percentage of budesonide in each stage of TSI is calculated from thestandard response for each test and the mean for the tests may becalculated to give an indication of the proportion of the activeparticles reaching the second stage of the TSI apparatus and thereforean indication of the proportion of active substance which would reachthe lower lung of a patient.

The variation in the measured values for the tests gives an indicationof the dose reproducibility for the inhaler and the dry powder used.

EXAMPLE 8

Micronised budesonide was blended with micronised L-leucine to produce apowder by the following method.

Budesonide and L-leucine were mixed to give a concentration of 1% byweight of leucine and the mixture was blended in a Turbula mixer for upto 30 minutes. The blend was passed through a 355 μm aperture diametersieve to improve mixing and to break up stable agglomerates to produce apowder having loose agglomerates of particles.

The resulting powder was weighed and filled into a Turbohaler inhalerdevice such that each actuation of the device dispensed about 200 μg ofpowder.

The above method was repeated to produce powders having 5% by weight ofleucine and 10% by weight of leucine.

The efficiency of the delivery of the active material for the powders bythe inhaler was then assessed using the TSI as described above.

Table 1 below shows the results of the TSI testing for each of thedifferent percent by weight of leucine. The respirable fraction iscalculated as the percentage of the total amount of drug emitted fromthe device that reaches stage two of the TSI and gives an indication ofthe proportion of active particles which would reach the deep lung in apatient. The standard deviation and the coefficient of variation arealso given.

TABLE 1 1% 5% 10% leucine leucine leucine Respirable fraction (%) 67.359.1 54.9 Standard deviation (%) 2.2 6.8 4.8 Coefficient of 3.3 11.6 8.7variation (%)

Where no leucine is added to the active powder, the respirable fractionis about 55%.

In addition, it will be seen that the coefficient of variation is low,especially for the powder containing 1% by weight of leucine indicatinggood reproducibility of the results (corresponding to improved doseuniformity of the administered drug). This indicates that the doseuniformity is also significantly better than for the currentlycommercially available Turbohaler product in which the powdercomposition does not contain the leucine additive material.

EXAMPLE 9

A powder was made by the method of Example 8, by blending micronisedbudesonide and 5% by weight of micronised L-leucine and 15% by weight ofSorbolac (a lactose powder having a particle size less than 63 μm ofMeggle Milchindustrie, Reitmehring Germany).

The resulting powder was assessed using the TSI.

Table 2 below shows the results of the TSI testing including therespirable fraction, the standard deviation and the coefficient ofvariation.

TABLE 2 5% leucine and 15% lactose Respirable fraction (%) 74.0 Standarddeviation (%) 3.1 Coefficient of 4.2 variation (%)

It can be seen that the addition of the lactose diluent significantlyincreased the respirable fraction and improved the dose uniformity.

What is claimed is:
 1. A powder for use in a dry powder inhaler, thepowder comprising active material and additive material, the additivematerial comprising an anti-adherent material including one or morecompounds selected from amino acids and derivatives thereof, andpeptides and polypeptides having a molecular weight of between about0.25 to 1000 kDa, and derivatives thereof, and the powder including atleast 60% by weight of active material based on the weight of the powderand further including not more than 10% by weight of additive materialbased on the weight of the powder, in which at least 90% by weight ofthe powder particles have a particle size of less than 63 μm.
 2. Apowder according to claim 1, wherein the additive material forms atleast a partial coating on the surfaces of particles of the activematerial.
 3. A powder according to claim 1, wherein the additivematerial includes an amino acid.
 4. A powder according to claim 1,wherein the powder comprises at least 80% by weight of active materialbased on the weight of the powder.
 5. A powder according to claim 1,wherein at least 90% by weight of the particles of the powder have aparticle size less than 10 μm.
 6. A powder according to claim 1, whereinthe additive material includes leucine.
 7. A powder according to claim1, wherein the additive material includes one or more water solublecompounds.
 8. A powder according to claim 1, wherein the additivematerial includes dipolar ions.
 9. A powder according to claim 1,wherein the additive material includes zwitterions.
 10. A powderaccording to claim 1, wherein the additive material includes greaterthan a glidant material.
 11. A powder according to claim 1, wherein theactive material includes a B₂-agonist.
 12. A powder according to claim1, wherein the powder comprises particles of active material andparticles of additive material.
 13. A powder according to claim 1,wherein the powder comprises at least 0.1% by weight of additivematerial on the weight of the powder.
 14. A powder according to claim 1,wherein the powder comprises not more than 5% by weight of additivematerial based on the weight of the powder.
 15. A powder according toclaim 1, wherein at least 95% by weight of the active particles have aparticle size of less than 10 μm.
 16. A powder according to claim 1,wherein at least 95% by weight of the active particles have a particlesize between about 0.1 μm and 5 μm.
 17. A powder according to claim 1,wherein the powder includes less than 20% by weight of constituentsother than the active material and the anti-adherent material.
 18. Apowder for use in a dry powder inhaler the powder comprising aβ₂-agonist as an active material and additive material comprising ananti-adherent material selected from leucine, L-leucine, D-leucine,DL-leucine, isoleucine, valine, methionine, cysteine, phenylalanine, andmixtures thereof, at least 95% by weight of the powder particles havinga particle size of less than 10 μm, the powder including at least 60% byweight of active materials based on the weight of the powder, andfurther including not more than 10% by weight of additive material basedon the weight of the powder.
 19. A powder according to claim 18, whereinat least 90% by weight of the powder particles have a particle size ofless than 30 μm.
 20. A powder according to claim 18, wherein the powderincludes at least 80% by weight of active particles based on the weightof the powder.
 21. A powder according to claim 18, wherein the powderincludes not more than 5% by weight of additive material based on theweight of the powder.
 22. A dry powder inhaler including a powdercomprising an active material, and an additive material, the additivematerial comprising an anti-adherent material selected from lecithin,leucine, L-leucine, D-leucine, DL-leucine, isoleucine, valine,methionine, cysteine and phenylalanine, and the powder including atleast 60% by weight of active material based on the weight of the powderand further including not more than 40% by weight of additive materialbased on the weight of the powder, in which at least 95% by weight ofthe active particles have a particle size less than 10 μm.
 23. A drypowder inhaler according to claim 22, wherein the powder inhalercomprises not more than 10% by weight of additive material based on theweight of the powder.
 24. A dry powder inhaler according to claim 22,wherein at least 95% by weight of the powder particles have a particlesize of less than 10 μm.